Many types of dosage forms have been developed in recent years in the field of external applications, and they have continued to attract a great deal of interest. This is because of a number of advantages, including the fact that local or systemic administration of a drug with an expected pharmacological effect through skin or a mucous membrane can provide a sustained drug effect, that adjustment of the absorption rate of the drug is easier so that side effects of overdoses can be prevented, that there is less of an effect of metabolism by initial passage through the liver as occurs with oral administration, and that administration can therefore be rendered relatively safer with drugs associated with liver damage, etc.
However, because normal skin has a protective function against stimulants from the outside, absorption and passage of drugs is comparatively more difficult. Consequently, it is presently the case that when drugs in external preparation form are administered their absorption is poorer and therefore their desired drug effects are more difficult to obtain.
Even by using absorption routes through biological membranes other than the skin, such as oral, rectal, buccal, nasal, sublingual, etc., there are still a great number of drugs which do not easily penetrate or pass through those biological membranes, and thus have low bioavailability.
Consequently, there is a demand for a highly useful and safe method for accelerating drug absorption, which sufficiently increases penetration, passage and absorption through the skin and other biological membranes to allow drug effects to be adequately exhibited at practically useful doses, and which itself results in minimal local toxicity or systemic toxicity.
Current absorption accelerating methods include accelerating methods employing absorbefacients and accelerating methods employing iontophoresis or phonophoresis. In particular, iontophoresis has rapidly attracted attention in recent years, and offers promise as a method of administration which can overcome the aforementioned problems.
Iontophoresis is a method of administering a drug through skin or a mucous membrane whereby a voltage is applied to the skin or mucous membrane to induce electrical migration of ionic drugs.
Iontophoresis electrode devices generally have a construction geared for therapy, whereby anode and cathode iontophoresis electrode devices are attached to the skin at a prescribed spacing, and the current generated from a current generator is fed to the electrode devices.
The electrode devices are constructed with the electrodes in combination with a layer which stores the drug or conducting medium, including a pre-designed fixed dose of the drug component together with various additives if necessary for stable maintenance of the drug effect, in order to administer a continuous controlled dose of the drug component to the body environment during a prescribed period.
When a current is applied to a membrane (such as skin) with polarization impedance, which has a low electrode reaction rate upon application of the current pulse or a low concentration of substances contributing to the electrode reaction, a polarization current is discharged upon termination of the pulse. Since the polarization current is a current flowing in the opposite direction from the current flowing by application of the pulse current, the net flow of current is the applied current minus the polarization current. This is the current responsible for penetration of the drug, and it is therefore defined as the transport current. A small transport current indicates poor efficiency in terms of drug penetration. Much research has been conducted with the purpose of solving these problems.
For example, in Japanese Laid-open Patent Publication No. 149168 of 1986 (hereunder referred to as Publication A) there is disclosed "an iontophoresis electrode device with an improved electrode, comprising a drug source to be supplied by ion introduction, means for carrying the drug source, and at least one electrochemically active component which is electrically connected with the drug source and undergoes a slight degree of hydrolysis during the ion introduction period", whereby the drug to be supplied by ion introduction, the electrochemically active component of the device, or both, are deliberately selected so as to reduce formation of undesirable hydrolysates during operation of the device.
In Japanese Laid-open Patent Publication No. 35266 of 1988 (hereunder referred to as Publication B) there is disclosed "an iontophoresis electrode device provided with a first electrode, a second electrode, means by which the first electrode communicates with a drug solution, means by which the drug solution communicates with a patient while said drug solution is situated between the first electrode and the patient, means by which the second electrode communicates with the patient at a distal point from the first electrode in the patient, and means by which a potential difference is created between the first electrode and second electrode in such a manner that the potential difference passes through the skin of the patient for transport of the drug ions, and by which an insoluble deposit is produced by reaction of the first electrode with the complementary ion, thus removing from the drug medium the ion which competes with the drug ion for charge transport and reduces the amount of drug administered to the patient", whereby the pH of the drug medium is controlled without a buffering agent to minimize production of the competing ion and thus maintain a dose of the administered drug in proportion to the current.
In Japanese Laid-open Patent Publication No. 502404 of 1988 (hereunder referred to as Publication C) there is disclosed "an iontophoresis electrode device provided with a first housing member containing an electrolyte, an electrode for the first housing member which contacts with the electrolyte in the housing member, a second housing member adjacent to the first housing member and designed to contain an effective component, an ion-exchange membrane as an ion migration-inhibiting member separating the first housing member and the second housing member, in order to inhibit the flow between the first and second housing members by ions with a charge equivalent to the effective component which has been at least partially ionized, and a support member for supporting the effective component in the second housing member when it passes through the skin of the patient to allow penetration of the ions of the effective component", the purpose of which is to increase the speed and efficiency of drug transport to the patient, and to reduce the chance of chemical burn injury which occurs by uncontrolled production of protons or hydroxide ions at the electrodes during ion introduction delivery of the drug, or of injury to the skin including electrical burn injury which occurs due to the use of high current.
In Japanese Laid-open Patent Publication No. 51062 of 1991 (hereunder referred to as Publication D) there is disclosed "an iontophoresis electrode device with a substance which reduces gas generation by hydrolysis situated on the surface of an cathode contacting with a drug solution", whereby the energy consumed by hydrolysis is minimized so that most of the electrical energy is utilized as drug delivery energy.
The following problems have become evident, however, with these constructions of conventional iontophoresis electrode devices. Specifically:
Since the devices described in Publications A and B employ electrochemically reactive electrodes, reuse of the electrodes has been difficult despite the low polarization, while the use of silver, etc. results in higher cost, and they have also been found to have problems of safety since metal ions from the electrodes tend to easily enter the body. Because the device described in Publication C employs an ion-exchange membrane, unnecessary entrance of ions into the body can be prevented, but ion-exchange membranes are generally expensive and also involve technical difficulties in their production. There has also been a problem of lower transport current due to polarization. The method of minimizing gas generation of the inert electrode disclosed in Publication D has had a problem in that polarization cannot be completely prevented, making it difficult to achieve satisfactory results.
When a buffering solution is used as the pH regulator to lower skin injury as described in Publication B, a problem has resulted in that the ions with buffering power enter into the body as electrification progresses, making it impossible to accomplish long-term electrification since the buffering power is lowered. Increasing the buffering power results in more competing ions, which is an undesirable problem in terms of drug penetration.
Consequently, there has been a demand for an iontophoresis electrode device which is safe, gives excellent performance, is reusable and can be produced at low cost.
The present invention overcomes these problems of the prior art and satisfies these demands, and its object is to provide an iontophoresis electrode device with superior performance which 1 is highly safe without entrance of metal ions from the electrode into the body, 2 is reusable and can be mass produced at low cost, 3 minimizes gas generation which causes polarization, for notably improved transport current, and 4can prevent skin injury by pH changes during prolonged application.